Cancer is second only to cardiovascular disease as a cause of death in the United States. According to the American Cancer Society, there will be an estimated 1,658,210 new cancer cases diagnosed and 595,690 cancer deaths in the US in 2016. (The Agency for Healthcare research and Quality (AHRQ) estimates that the direct medical costs (total of all health care costs) for cancer in the US in 2011 were $88.7 billion.
Modalities useful in the treatment of cancer include chemotherapy, radiation therapy, surgery, immunotherapy, and other gene-, protein- or cell-based treatments. Conventional cancer therapies have many drawbacks including toxicity and significant side effects often limit the ability of patients to continue treatment, including immunosuppression, and damage to vital organs. Cancer cells eventually develop multi-drug resistance after being exposed to one or more anticancer agents. Most chemotherapeutic drugs act as anti-proliferative agents, targeting different stages of the cell cycle, thereby interfering with the function of healthy tissues and organs. Given the differing sensitivity of tumor cells to treatment, the ability of tumors to mutate and adapt to therapies, as well as the plethora of mechanisms that the tumor uses simultaneously in order to subvert host defenses, it is commonplace for multi-drug regimens to be used in cancer treatment. In turn, drug interactions and side effects that patients must contend with can increase exponentially.
Innumerable researchers and companies have searched for improvements in the treatments for the wide array of cancers. Companies are advancing bioactive agents including chemical entities, e.g., small molecules, and biologics, e.g., antibodies, with the desire of providing more beneficial therapies for cancer. Some bioactive agents have worked and provided beneficial therapeutic effects in some individuals or cancer types and others have failed or had minimal therapeutic effects or side effects that precluded completion of treatment due to organ toxicity, acute events such as thrombosis, and/or patient intolerance.
Analysis of the immunologic features of the tumor microenvironment is enabling rapid development of multiple new therapeutic strategies against various types of cancer as well as the identification of potential biomarkers for clinical benefit. Some cancers display hundreds or even thousands of mutations in coding exons, representing a large repertoire of antigens to serve as potential targets for the immune system. However, despite these abundant antigens, most cancers can evade immune mediated rejection, despite the ability to detect spontaneous anti-tumor immune responses in the majority of cancer patients (Gajewski, T. F., H. Schreiber, and Y. X. Fu, Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol, 2013. 14(10): p. 1014-22), which is incorporated herein by reference in its entirety.
There is an emerging portfolio of inhibitory checkpoints that can influence the physiology of innate immune cells including dendritic cells, macrophages, natural killer (NK) cells, and T cells to harness their effector function in order to over-ride the tumor's inhibitor signals. A focal point of cancer therapeutics is therefore the discovery of novel therapeutic strategies of fine tuning and augmenting the appropriate anti-tumor responses. Moreover, it is known in the art that a synergistic combination of strategies directed toward overcoming the cancer's immune inhibitory signals and stimulating the endogenous anti-cancer immune response is believed to offer therapeutic advantages. Finding the right combinations of drugs to effectively treat a particular cancer, as well as limiting toxicity, have remained the two major thrusts in the art of clinical cancer research.
Different polyphenolic compounds of natural origin, such as trans-resveratrol (trans-3,5,4′-trihydroxystilbene, t-RESV), have been studied for their potential antitumor properties (3). Resveratrol (trans- or (E)-3,5,4′-trihydroxystilbene (1)) is a phytoalexin produced in plants and popularized as a beneficial ingredient of red wine. Resveratrol, its cis- or (Z)-isomer (2), and another stilbene derivative, pterostilbene (3), exhibit some anti-cancer activity. Cancer chemopreventive activity of t-RESV was first reported by Pan et al. (4). However, anticancer properties of t-RESV are limited due to the low systemic bioavailability of t-RESV (5). Thus, structural modifications of the t-RESV molecule appeared necessary in order to increase the bioavailability while preserving its biological activity. Resveratrol has also been produced by chemical synthesis and is sold as a nutritional supplement derived primarily from Japanese knotweed.